Axitinib (1) is a vascular endothelial growth factor (VEGF) inhibitor. These kinds of antagonists have been recognized as an important class of pharmaceutical agents for development due to their efficiency in controlling the growth and proliferation of cancer cells. INLYTA®, containing Axitinib as its active ingredient, was approved by the Food and Drug Administration (FDA) in 2012 for the treatment of patients with advanced renal cell carcinoma (RCC).

WO 01/02369 A2 describes indazole compounds that modulate and/or inhibit the activity of certain protein kinases. These compounds, and pharmaceutical compositions containing them, are capable of mediating tyrosine kinase signal transduction and thereby modulate and/or inhibit unwanted cell proliferation. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds, and to methods of treating cancer and other disease states associated with unwanted angiogenesis and/or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis, by administering effective amounts of such compounds.
U.S. Pat. No. 7,232,910 B2 relates to methods for preparing indazole compounds, which are useful as modulators and/or inhibitors of protein kinases. U.S. Pat. No. 7,232,910 also relates to intermediate compounds useful in the preparation of such compounds.
WO 2006/048745 A1 relates to methods for preparing indazole compounds or pharmaceutically acceptable salts or solvates thereof. Such compounds are useful as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer or other diseases associated with cellular proliferation mediated by protein kinases.
Org. Process Res. Dev., 2008, 12(4), 637-645 describes that AG13736 (Axitinib), an inhibitor of vascular endothelial growth factor (VEGF) under investigation as an oncology drug, is currently manufactured via a three-step process that utilizes two palladium-mediated cross-couplings. Historically, removal of residual heavy metals from the active pharmaceutical ingredient has been a persistent issue. The development of a much improved process for palladium removal and a useful screening technique developed to rapidly identify the most efficient reagents for this purpose are outlined. The performance of the new endgame process in pilot-plant scale-up is also discussed.
US 2009/062347 A1 describes deuterium-enriched Axitinib, pharmaceutically acceptable salt forms thereof, and methods of treating using the same.
Org. Process Res. Dev., 2014, 18 (1), 266-274 describes a manufacturing process of Axitinib involving two Pd-catalyzed coupling reactions, a Migita coupling and a Heck reaction. Optimization of both of these pivotal bond-formation steps is discussed, as well as approaches to control the impurities present in the prepared Axitinib. Essential to the control strategy was the optimization of the Heck reaction to minimize formation of impurities, in addition to the development of an efficient isolation of crude Axitinib to purge impurities.
CN 103570696 relates to a method for preparing an intermediate of Axitinib and the application of this intermediate in the preparation of Axitinib. The preparation method for the intermediate of Axitinib, 3-iodo-6-nitro-1-(tertrahydro-2H-pyran-2-yl)-1H-indazole, comprises the following steps: first, 6-nitroindazole and 3,4-dihydro-2H-pyran are reacted under the action of a catalyst to protect the indazole at its N—H site; and, second, the iodination occurs at the 3-position. The intermediate may then be used in the preparation of Axitinib as follows: first, a Heck coupling reaction is carried out on the intermediate with 2-vinyl pyridine; second, the 6-nitro group is reduced and converted to an iodo group; and finally, Axitinib is obtained after the docking of 2-sulfydryl-N-methyl benzamide at the 6-position and deprotection of the indazole nitrogen. The initial raw materials for the process are available commercially and the method provides a high yield and high molecule economic efficiency, is efficient, environment-friendly, and is suitable for industrial mass production. However, the process of CN 103570696 still relies on the use of palladium-catalyzed reactions, which necessitates removal of the palladium before the product can be used as a pharmaceutical.